Pirfenidone and Nintedanib for Treatment of Idiopathic Pulmonary Fibrosis

Gayathri Sathiyamoorthy, MD; Sameep Sehgal, MD; Rendell W. Ashton, MD

Disclosures

South Med J. 2017;110(6):393-398. 

In This Article

Pirfenidone

Pirfenidone is a synthetic drug with antifibrotic, anti-inflammatory, and antioxidant properties.[4] Some of the proposed mechanisms of pirfenidone's antifibrotic activity include its ability to inhibit the production and activity of transforming growth factor-beta[5] and inhibit the production of platelet-derived growth factor by macrophages.[6] The exact mechanism of action of the drug in treating IPF in humans is unclear, however. Pirfenidone was approved for the treatment of IPF in the United States in October 2014 based on the positive results of multiple clinical trials between 2005 and 2014.[7–10]

Important Clinical Trials

The first phase II randomized trial[7] comparing pirfenidone with placebo in 107 patients with IPF failed to reach its primary endpoint of decreased desaturation during a 6-minute walk test (6MWD); however, the trial demonstrated that patients receiving pirfenidone had fewer exacerbations than those taking a placebo and experienced a significantly slower decline of their forced vital capacity (FVC). These observations led to a trial in 275 patients by Taniguchi et al.[8] In this study, the pirfenidone group showed a significantly slower decline in their FVC compared with the placebo group. The study also looked at many secondary endpoints, including progression-free survival (PFS). Disease progression was defined as either death or >10% decrease in FVC. The pirfenidone group showed a significantly increased PFS time. Despite the promising results, this study was criticized because of the statistical methods used to address missing data and a change in the primary endpoint at the conclusion of the study.

The Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) trials (studies 004 and 006) were nearly identical large, multinational studies conducted in the United States, Europe, and Australia.[9] They evaluated the efficacy of pirfenidone compared with placebo in 779 patients with IPF in a period of 72 weeks. The primary endpoint was the change in percentage of predicted FVC. The two studies had inconsistent results.[9] Study 004 showed a decreased decline of FVC in the pirfenidone group, whereas study 006 showed no significant difference. The studies also showed a trend toward fewer overall deaths and fewer deaths related to IPF in the pirfenidone groups compared with the placebo groups, but these results were not statistically significant.

The inconsistent results of the CAPACITY trials prompted another phase III study in the United States called the Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF (ASCEND) trial.[10] A total of 555 patients were enrolled and studied for 52 weeks for a primary endpoint of change in percentage of predicted FVC at 52 weeks. In the pirfenidone group, the absolute decline of ≥10% of the predicted FVC or death was reduced by 47.9% compared with the placebo group (P < 0.01). The mean decline from baseline in the FVC was 235 mL in the pirfenidone group compared with 428 mL in the placebo group, a relative difference of 45.1% (P < 0.001). Pirfenidone also reduced the decline in 6MWD (P = 0.04) and improved PFS (P < 0.001). These treatment effects were evident by week 13 and increased throughout the duration of the study; there was, however, no significant difference between the groups' dyspnea scores at week 52. Although all-cause mortality showed fewer deaths in the pirfenidone group compared with the placebo group, this was not statistically significant (P = 0.10). When the patients from the CAPACITY and ASCEND trials were pooled (1247 patients), pirfenidone reduced the risk of all-cause mortality by 48% and death related to IPF by 68% at 1 year (P = 0.01 and P = 0.006, respectively).

Various subgroup analyses of the major studies have been performed. In one such study,[11] it appeared that pirfenidone was most effective in patients with relatively mild impairment in lung function (FVC ≥70% of predicted level). In another analysis,[12] pirfenidone had its greatest effects on patients with mild to moderate impairment in lung function (FVC ≥70% of predicted) whose oxygen saturation fell to <90% during a 6MWD.

Based on these studies and systematic reviews,[11,12] it has been concluded that pirfenidone reduces disease progression (as measured by the changes in FVC and 6MWD) and improves PFS (time to first IPF exacerbation or death) in patients with mild to moderate IPF. Pirfenidone has not been shown to affect respiratory symptoms or mortality.

Adverse Reactions

Pirfenidone was discontinued as a result of adverse effects in 15% of patients (11 of 73 patients) in the initial trial by Azuma et al,[7] when a dose of 20 to 30 mg/kg/day was used. In the ASCEND trial, 19.8% of the subjects discontinued pirfenidone; however, 14.1% of those receiving placebo discontinued their study drug as well. Adverse skin and gastrointestinal effects were seen most commonly in the pirfenidone group but were generally mild to moderate in severity, with only 2.9% and 2.2% of patients, respectively, having to discontinue the medication as a result of these adverse events. Liver enzyme elevation occurred in 3% of patients; however, this increase did not have significant clinical consequences and was reversible.[10]

Common adverse effects reported in the CAPACITY and ASCEND trials include nausea (36%), abdominal discomfort (24%), dyspepsia (19%), diarrhea (22%), rash (28%), and photosensitivity (9%). Fatigue, headache, fever, dizziness, and insomnia also were observed in >10% of patients.[9,10]

Patients should be advised to ingest the medication with meals because it reduces the severity of adverse gastrointestinal effects. If patients develop significant symptoms or liver function abnormalities, then the medication dose can be reduced and subsequently increased slowly to the target dose. Patients also should be advised to limit exposure to sunlight and to wear protective gear and sunscreen when going out to avoid significant photosensitivity reactions.

Drug Interactions/Special Considerations

Pirfenidone is mainly (70%–80%) metabolized in the liver by CYP1A2 enzymes. Ciprofloxacin, fluvoxamine, and other inhibitors of the CYP1A2 enzyme may increase the dose of pirfenidone and increase the risk of adverse reactions.[13] These interactions should be avoided or the dose of pirfendione should be reduced in patients who must take medications that inhibit the CYP1A2 enzyme. Patients should be instructed to stop smoking because drug clearance may be increased and systemic exposure decreased in cigarette smokers as a result of hepatic enzyme CYP1A2 induction.[14]

Pirfenidone was not studied in patients with advanced liver or renal disease. The drug is not recommended for patients with end-stage liver disease (Child-Pugh class C) or end-stage renal disease requiring dialysis. The Risk Evaluation and Mitigation Strategy program requires that liver function test (LFT) monitoring be conducted monthly for 3 months and then every 3 months thereafter.

Dosing

Pirfenidone is available in a 267-mg immediate-release capsule. It is taken three times per day, and during a 2-week dose escalation period the drug is titrated up to the goal dose of 2403 mg/day (9 capsules) to be taken with food.[14] The titration scheme was proposed to limit adverse effects such as nausea, dyspepsia, and dizziness. In our ILD clinic, we sometimes recommend a longer titration period, depending upon the patient's tolerance to the drug.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....